TNF receptors have multiple roles in shaping adaptive and innate immune responses, and dysregulation of multiple TNF family members has been shown to be critical in the pathogenesis of many rheumatic diseases. The lab has two main interests: 1) Biology of TNF-family receptors in lymphocytes and mouse models of autoimmunity 2) Understanding the molecular pathogenesis of single-gene autoimmune and autoinflammatory diseases. We are currently studying the biology of three members of the TNF-R superfamily in detail: TNFR1, Fas/CD95, and DR3. For TNFR1 we are concentrating on the pathogenesis of inflammation associated with TNFR1 and the TNFR1-associated periodic syndrome (TRAPS). We have found that TNFR1 mutation causes receptor misfolding and ER retention that may lead to inflammation through novel TNF-independent mechanisms. For the apoptosis-inducing receptor Fas, we are studying cell intrinsic and extrinsic factors that regulate the efficiency of Fas-induced apoptosis in vitro and in vivo. For DR3, we are defining the pattern of expression and function of DR3 and its ligand TL1A in a number of model systems. In a collaborative project supported by a Bench-to-Bedside initiative, we are examining the pathogenesis of autoimmunity in the Wiskott-Aldrich Syndrome.